Chemical compounds

ABSTRACT

The invention provides 3 Alpha -oxygenated pregnane 21-ethers possessing a hydroxy group in the 3 Alpha -position; a hydrogen atom or a methyl group at the 10-position; a hydrogen atom in the 17 Alpha -position; a keto group in the 20-position; and an etherified hydroxyl group in the 21-position.

Umted States Patent 1 1 1 3,882,151 Phillipps et al. 1 May 6, 1975 [54]CHEMICAL COMPOUNDS 3,652,554 3/l972 Anner et 260/239.55 1 Gordon HurleyPhillip, wembley; 33% T1133? 522i;iffliijiiji:iiijiiijiiiiiifflliifiiiChristopher Earle Newall, London, both of England OTHER PUBLICATIONS[73] Assign: Glam Laboratories Limited Harnik et 3]., Anal. Biochem,15(1), I966, pp. Greenfmd, Mlddlesex England 175-176; CA v01. 65, I966,par. l7,0l8(h) to par. 22 Filed: Dec. 16, 1971 [21] Appl. No.: 208,961

Primary ExaminerElbert L. Roberts Attorney, Agent, or FirmBacon & Thomas[30] Foreign Application Priority Data Dec. 17, I970 United Kingdom60065/70 [57] ABSTRACT [52] The invention provides 3q-oxygenatedpregnane 2|- 51] In Cl c 67/00 ethers possessing a hydroxy group in theIla-position; a [58] Field 260/397 45 hydrogen atom or a methyl group atthe lO position; a hydrogen atom in the Hal-position; a keto group in[56] References cued the 20-position; and an etherified hydroxyl groupin the 2 1 -position.

13 Claims, No Drawings CHEMICAL COMPOUNDS This invention is concernedwith improvements in or relating to compounds of the pregnane serieshaving useful anaesthetic activity.

It has long been known that a number of steroids give rise to profounddepression of the central nervous system and act pharmacodynamically asanaesthetics or hypnotics. Such compounds have been the subject ofconsiderable study in an attempt to find anaesthetics to replace suchsubstances as thiopentone sodium, normally used but well known to beaccompanied by some degree of hazard and disadvantage. The literatureshows that very many steroid compounds have been studied in this regard.Reviews and discussions of some of the work carried out are to be found,for example, in Methods in Hormone Research" (Edited by Ralph l.Dorfman, Vol. III, Part A, Academic Press, London and New York, 1964,pages 415-475); H. Witzel, Z. Vitamin Hormon-Fermentforsch 1959,10,46-74; H. Selye, Endocrinology, 1942, 30, 437-453; S.K. Figdor etal., J. Pharmacol. Exptl. Therap., 1957, l 19,299-309 and Atkinson etal., J. Med. Chem. 1965, 8 426-432.

A thorough review of the literature indicates that anaesthetic steroidsgenerally possess poor activity and/or long induction periods. With suchcompounds a variety of undesired side effects such as paraesthesia andvein damage have also been noted. Steroids possessing anaestheticactivity hitherto described are generally relatively simple pregnanederivatives, often hydroxylated in the 3-position, the general trendhaving been in the latter case to study 3B-hydroxy compounds rather than3a-hydroxy compounds.

We have now found that certain new compounds of the pregnane serieswhich possess inter alia a 3&- oxygenated-2 l -ether structure and whichare more particularly described hereinafter have remarkable anaestheticproperties.

The aforesaid 3a-oxygenated pregnane 2l-ethers may be generallycharacterised as being steroids of the pregnane series havinganaesthetic properties and further characterised by possessing a hydroxyor acyloxy group in the a-configuration at the 3-position; an oxo groupand preferably at the ll-position', a hydrogen atom at the 17a-position;a keto group at the 20- position and an etherified hydroxy group at the21- position.

The etherified hydroxy group at the 2l-position is preferably asaturated or unsaturated aliphatic, cycloaliphatic, araliphatic,aromatic or heterocyclic hydrocarbyloxy group which may if desired, besubstituted.

The expression pregnane series as used herein includes not onlycompounds of the conventional pregnane (5a or 58, particularly theformer) ring structure, if desired possessing unsaturation, but also thecorresponding l9-nor compounds, the presence or absence of a methylgroup at the lO-position having little influence on anaestheticproperties.

The above-defined 3a-oxygenated pregnane 2 l -ether anaesthetics havebeen found to induce anaesthesia with generally short induction periods,the anaesthetic action in general being at suitable doses virtuallyinstantaneous; the compounds are thus excellent anaesthetics forinducing anaesthesia which is to be maintained e.g. by an inhalationanaesthetic such as ether, halothane, nitrous oxide, trichloroethyleneetc. The

compounds are however capable of maintaining anaesthesia and analgesiato a sufficient degree to enable various surgical operations to beconducted without the aid of an inhalation anaesthetic, the requireddegree of anaesthesia being maintained if necessary by repeatedadministration (or even continuous administration). Moreover, the saidanaesthetics in accordance with the invention in general give rise tominimal side-effects compared to previously described steroidalanaesthetlcs.

Certain of the new compounds according to the invention may also serveas solubilisers for the anaesthetic steroidBa-hydroxy-Sa-pregnane-l1,20-dione in analogous manner to the 21-acyloxycompounds described in our Belgian Patent No. 752,165. Thus we havefound it possible to prepare solutions of 3ahydroxy-Sa-pregnane-l1,20-dione, in for example aqueous solutions of parenterally acceptablesurface active agents, having as solubility promoter 3ahydroxy-2 l-propoxy-5a-pregnane-l 1,20-dione. In this manner the solubility of3a-hydroxy-5a-pregnanel 1,20-dione may be increased several-fold.

The invention further includes Zia-esters of the above-definedSa-hydroxy-pregnane 2l-ethers, particularly lower alkanoyl esters, forexample, containing in the alkanoyl group up to 5 carbon atoms, e.g. theacetate. Such esters may also be esters containing one or moresubstituents in the alkanoyl portion e.g. halogen atoms, carboxy groups,amino groups etc., or salts thereof when a substituent capable offorming a salt with an acid or a base is present. Generally theinduction period of a 3-ester is longer than that with a correspondingZia-hydroxy compound. Both the 3a-hydroxy compounds and thecorresponding 3-esters may be regarded as central nervous systemdepressants and thus in suitable doses may also be used as hypnotics orsedatives.

The above defined 3oz-hydroxy2l-ether-pregnane compounds and thecorresponding 3a-esters are hereinafter collectively referred to asSoc-oxygenatedpregnane 21 -ether anaesthetics.

The 3a-oxygenated-pregnane-2l-ether anaesthetics may contain furthersubstitution, for example at the 16- position. Examples of substituentswhich may be present at position 16 include either one or two alkylgroups, especially lower (e.g. having l-6 carbon atoms) alkyl groups,for example methyl groups.

The compounds of the invention may also be substituted at the 2Bpositionfor example by an acyloxy group containing for example 1-9 carbon atoms,an ether or thioether group (i.e. the residue of an alcohol, a phenol ora thiol) containing for example l-9 carbon atoms (e.g. methoxy), analkyl or cycloalkyl group for example containing up to 9 carbon atoms,an aryl group (e.g. a phenyl group), an aralkyl group (e.g. a benzylgroup), a hydroxy group, a thiocyanato group, a nitro-oxy group, or ahalogen atom. Acyloxy substituents (which may be saturated orunsaturated) include lower (C -C alkanoyloxy groups, (substituted ifdesired, for example, with one or more halogen, e.g. chlorine, atoms,lower alkoxy, amino or substituted amino groups), aroyloxy groups, e.g.a benzoyloxy group, or aralkanoyloxy groups, e.g. a phenylacetoxy group.Ether substituents, which may be saturated or unsaturated, include lower(C C alkoxy groups, lower alkenyloxy groups (e.g. an allyloxy group)cycloalkoxy groups, e.g. a cyclohexyloxy group, aryloxy groups, e.g.

a phenoxy group, and aralkoxy groups, e. g. a benzyloxy group. Thioethergroups corresponding to the abovementioned ether groups arerepresentative of 2B- thioether substituents.

The 2B-substituent may alternatively be an azido, sulphonyloxy (e.g.tosyloxy) group or an acylthio group.

Example of ZB-alkyl groups include especially lower alkyl groupscontaining 1-5 carbon atoms such as methyl, ethyl, propyl, butyl,isobutyl and t-butyl groups. An example of a cycloalkyl group is acyclohexyl group.

Examples of lower alkanoyloxy ZB-Substituents include acetoxy,propionyloxy, butyryloxy groups, piperidinoacetoxy, morpholinoacetoxy,diethylaminoacetoxy and chloroacetoxy. Examples of lower alkoxy groupsinclude methoxy, ethoxy, propoxy, isopropoxy n-butoxy and t-butoxygroups, and the corresponding thio compounds exemplify lower alkyl thiosubstituents.

Lower alkoxy and lower alkylthio substituents at the 2B-position maythemselves be substituted for example by one or more halogen (e.g.chlorine) atoms, lower alkoxy, esterified carboxyl (e.g.ethoxycarbonyl), hydroxy, amino or substituted amino, e.g. morpholinogroups, or substituted or unsubstituted acyloxy, e.g. morpholinoacetoxy,chloroacetoxy or diethylaminoacetoxy, or heterocyclic groups, e.g. atetrahydrofuranyl group. Alkyl, cycloalkyl and aryl groups may also besubstituted.

The ZB-pcsition may also carry amino substituents, e.g. amino orsubstituted amino groups, for example monoor di-alkylamino or saturated,unsaturated or aromatic heterocyclic groups, e.g. a morpholino groupParticularly useful anaesthetic compounds in accordance with theinvention are the 21-ethers of 3a,2ldihydroxy-Sapregnane-l l ,ZO-dione.

The 2] -ether substituent is preferably an alkoxy, cycloalkoxy, aralkoxyor aryloxy group which may carry substituents such as primary, secondaryor tertiary amino groups, including heterocyclic groups, or carboxyl andesterified carboxyl groups, cyano groups and halogen atoms, e.g.chlorine atoms.

The amino substituent is conveniently a group of formula NRR wherein Rand R, which may be the same or different, each represents a hydrogenatom or a lower (C -C alkyl group or R and R together with the adjacentnitrogen atom represent a 5- or 6- membered heterocyclic group e.g. apiperidino, piperazino or morpholino group which may, if desired, besubstituted by at least one alkyl group; examples of such groups includean amino group, a methylamino group, a dimethylamino group, anethylamino group, a diethylamino group or an N- methylpiperazine group.

A particularly preferred group of the above compounds are those whereinthe 2l-ether group is a lower alkoxy (C -C group, which may besubstituted, e.g. by a lower alkoxy (C -C.) group; examples of suchgroups are methoxy, ethoxy, n-propoxy, isopropoxy and methoxyethoxygroups. Other compounds according to the invention are compounds whereinthe 21- ether group is a phenoxy, cyclopentyloxy or benzyloxy group.

One group of preferred compounds in accordance with the invention arecompounds carrying at least one primary, secondary or tertiary aminogroup or at least one carboxyl group, the invention including non-toxicsalts of such compounds. By the term non-toxic" as applied to thecompounds of the invention we means those derivatives which arephysiologically acceptable in the dosage at which they are administered.As will be appreciated, amino and carboxy substituents of the type justreferred to permit the formation of salts tending to improve thewater-solubility of the steroid. Such salts include, in the case ofamino-substituted compounds, hydrochlorides, hydrobromides, phosphates,sulphates, p-toluenesulphonates, methanesulphonates, citrates andtartrates. in the case of carboxy-substituted compounds, examples ofsalts include alkali metal, e. g. sodium or potassium salts and ammoniumsalts and other salts formed with physiologically compatible amines.

Examples of aminoor carboxy-substituted 2l-ether groups includep-arninophenoxy, carboxyphenoxy, diethylaminoethoxy, morpholinoethoxy,carboxyethoxy and N-methyl-piperazinoethoxy groups.

Particularly preferred compounds according to the invention by virtue oftheir excellent anaesthetic properties are:

3a-hydroxy-2 l -n-propoxy-5a-pregnanel l ,20-dione;

3a-hydroxy-2 l -methoxy-5a-pregnane-l l ,ZO-dione; 21-ethoxy-3a-hydroxy-5a-pregnane-l l ,ZO-dione; 3a-hydroxy-2 l2-methoxyethoxy )-5a-pregnane -l 1,20-dione;

2 l 2-chloroethoxy )-3a-hydroxy-5a-pregnane- 1 1,20-dione;

2 l 3-chloropropoxy-3a-hydroxy-5a-pregnanel 1,20-dione;

2 l-cyclopentyloxy-Sa-hydroxy-Sa-pregnane-l I ,20-

dione; and

3a-hydroxy-2 l -methoxyl 6a-methyl-5a-pregnanel 1,20-dione.

The above-defined 3a-oxygenated-pregane-2 l -ether anaesthetics may beformulated as convenient, following generally known pharmaceuticalpractices, (including both human and veterinary medical practices), withthe aid of one or more pharmaceutical carriers or excipients. Foranaesthetic purposes, the steroids will be given by injection and thusone aspect of this invention comprises an anaesthetic composition forparenteral administration comprising a Zia-oxygenated-Zl-etherpregnaneanaesthetic as above-defined in a parenter ally acceptable vehicle.

Many of the' above-described 3a-oxygenated-2l ether-pregnaneanaesthetics are poorly soluble in water. We have found however thatthey may be formulated for parenteral administration in an aqueoussolution of a parenterally acceptable non-ionic surface active agent.These surface active agents may also be used even where the steroid issufficiently water soluble as they may reduce the risk ofthrombophlebitis.

The non-ionic surface active agents used for the purpose of thisinvention are generally those of the watersoluble type, convenientlyhaving an HLB value of at least 9, preferably at least about 12,advantageously at least about 13. Preferably the HLB value of thesurface active agent is not greater than about 15 although it may, forexample, be as high as 18. The surface active agent must naturally beone which is physiologically compatible, i.e. of itself give rise to nophysiologically unacceptable side effects in the dosages employed in theintended species to be treated (man or animal). Surface active agentsfor use in accordance with the in vention are for example to be foundamong the following non-ionic surfactants and classes of surfactants:Po-

lyoxyethylated derivaties of fatty (Cl 2-C20) glyceride oils, e.g.castor oil, containing from 35 to 45 or even up to 60, oxyethylenegroups, per mole of fatty oil. Polyoxytheylene ethers (containing fromto 30 polyoxyethylene groups) of long chain alcohols (containing forexample from 12 to 18 carbon atoms).

Polyoxyethylene-polyoxypropylene ethers containing from to 35 and from15 to 30 oxyethylene and oxypropylene groups respectively.polyoxyethylene ethers (containing from 6 to l2 oxyethylene groups) ofalkyl phenols the alkyl groups of which preferably contain 6-10 carbonatoms.

Polyoxyethylated (containing from 15 to 30 oxyethylene groups) fattyacid (e.g. Cl2-l8) esters of sugar alcohol anhydrides e.g. sorbitan ormannitan. Longchain (e.g. C1046) alkanoyl monoand dialkanolamides (thealkanol portions of which for example contain l-5 carbon atoms) forexample lauroyl monoand di-ethanolamides. Polyethylene glycol esters(containing from 6 to 40 ethylene oxide units) of long chain fatty acids(containing for example 12-18 carbon atoms) e. g. polyethyleneglycolmonooleate (containing for example 8 ethylene oxide units).

Examples of non-ionic surface active agents, of the foregoing types,useful in accordance with the invention include:

Cremophor EL, a polyoxyethylated castor oil containing about 40 ethyleneoxide units per triglyceride unit;

Tween 80, polyoxyethylene sorbitan monooleate containing about ethyleneoxide units;

Tween 60, polyoxyethylene sorbitan monostearate containing about 20ethylene oxide units; and

Tween 40, polyoxyethylene sorbitan monopalmitate containing about 20ethylene oxide units.

The expression solutions is used herein to denote liquids which have theappearance of true solutions and are thus optically clear and capable ofpassage, for example, through a micro-porous filter, irrespective ofwhether such solutions are true solutions in the classical chemicalsense and irrespective of whether they are stable or metastable. Thus itmay be that the steroid is associated with micelles. The solutions ofthis invention, irrespective of their precise physical nature, behave astrue solutions for the practical purpose of intravenous injection.

The proportion of surface active agent to be used in the compositions ofthis invention depends upon its nature and upon the concentration ofsteroid desired in the final composition.

In preferred compositions according to the invention the proportion ofsurfactant is preferably at least 5% by weight and advantageously above10% by weight. A very convenient proportion of surfactant has been foundto be 20% by weight but and up to 50% may be used. The proportions ofsurfactant are expressed by weight in relation to the total volume ofthe composition.

As will be clear, the proportion of steroid which is dissolved in theaqueous solution according to the invention depends upon the nature andamount of surface active agent used. The composition will generallycontain at least 1 mg/ml of steroid and solutions can be made containingfor example up to 7 mg/ml of steroid or even 10 mg/ml.

In one method of preparing the solutions according to the invention thesteroid is first dissolved in the selected surfactant, for example withheating, and the resulting solution dissolved in water. Alternativelythe steroid may be dissolved in a volatile organic solventadvantageously having a boiling point of less than about C which ismiscible with the surface active agent such as a volatile loweraliphatic ketone e.g. acetone or methyl ethyl ketone or a volatilehalogenated hydrocarbon e.g. chloroform or methylene chloride. Thesurface active agent is then added to this solution, the organic solventremoved by evaporation, for example by passing a stream of an inert gasthrough the solution e.g. nitrogen and the resulting solution of steroidin surfactant is mixed with water.

The solutions may also be prepared by shaking the steroid with anaqueous solution of the surface active agent.

In all cases simple tests enable one to determine the relativeproportions of surface active agent required.

The anaesthetic solutions according to the invention are generallyadministered by intravenous injection although as is known in theanaesthetic art in certain cases, e. g. with young children,intramuscular injection might be preferred.

As is usual in the case of anaesthetics, the quantity of steroid used toinduce anaesthesia depends upon the weight of the individual to beanaesthetised. For intravenous administration in the average man a doseof from 0.5 to 30 mg/Kg will in general be found to be satisfactory toinduce anaesthesia, the preferred dose being within the range of from0.7 to 20 mg/Kg. The dose will naturally vary to some extent dependentupon the physical condition of the patient, and the degree and period ofanaesthesia required, all as is well known in the art. It is thuspossible by adjustment of the dose to achieve durations of anaesthesiavarying from about 10 minutes to up to an hour or more. If it is desiredto maintain prolonged anaesthesia, repeated doses of the solutions ofthis invention may be used, such repeated doses being generally eitherof the same order or lower than the original dose. Alternativelycontinuous administration may be undertaken at for example a rate of0.09-l.4 mg/Kg/Min.

Where the anaesthetic solutions are administered intramuscularly, higherdoses are generally necessary.

The new compounds according to the invention may be prepared inprinciple by the reaction of an appropriately substituted2l-hydroxy-pregnane compound or a reactive derivative thereof with analcohol or phenol (or reactive derivative thereof) to form the desiredether group. It will be appreciated that the formation of the etherlinkage at position 21 may be effected as a final step in the synthesisof the desired compound, or alternatively at some intermediate stageduring the elaboration of the desired molecule, subsequent stagesinvolving for example introduction of additional substitution, e.g. atthe 2B-position.

The ether linkage at position 21 may be formed in conventional manner,general methods for the formation of ethers being described for examplein the textbook Chemistry of the Ether Linkage" by Saul Patai(lnterscience Publishers, London, New York and Sydney, 1967).

In one embodiment of the above method, the 2]- hydroxy steroid or thesaid alcohol is reacted with a diazo derivative of the other reactant toform the desired ether.

Thus for example a 21 -diazo-pregnan-20-one may be reacted with anappropriate alcohol, in conventional manner, if desired in the presenceof a catalyst, e.g. cupric oxide or boron trifiuoride. This reaction,which is particularly suitable for the production of aliphatic andaraliphatic ethers is conveniently carried out in a solvent medium whichmay be an excess of the etherifying alcohol or a further co-solvent, forexample an ether such as diethyl ether, tetrahydrofuran or dioxan, or ahalogenated hydrocarbon, e.g. methylene chloride, chloroform etc, underanhydrous conditions.

Generally the reaction is effected at elevated temperature for exampleat the boiling point of the solvent used.

The diazo ketones required as starting materials are convenientlyprepared in conventional manner from the correspondingl7/3-chlorocarbonyl steroids (preferably in the presence of a tertiaryorganic base such as triethylamine) with a diazoalkane.

During the formation of the acid chlorides, the conversion to thesubsequent diazo ketones and the subsequent reaction to form the ether,it may be desired to protect the 3a-hydroxy group.

Protection of Ba-hydroxy groups can be effected in conventional mannerwith the formation of a readily removable protecting group e.g. anitrate, silyl, or acyl group. The protective group at position 3 can beremoved in conventional manner, as desired, by, for example, hydrolysisor reduction as may be appropriate to the particular protective group,all as is well known in the art.

In a further embodiment of the above method of preparing the ethers inaccordance with the invention the appropriate ZI-hydroxy-pregnanecompound may be reacted with a diazo compound, for example adiazoalkane, such as diazomethane in conventional manner. This reactionis carried out in generally similar manner to the above-describedreaction of a steriod 21-diazo- ZO-ketone using a catalyst as may benecessary, for example boron trifluoride.

In yet a further embodiment a 2 l-halo-pregnane compound, e.g. a2l-bromoor 2l-iodo compound may be reacted with a metal derivative ofthe etherifying hydroxylic compound. Suitable metal derivatives arealkali metal, e.g. sodium or potassium derivatives, the reaction beingparticularly applicable to the formation of ethers from aromatic hydroxycompounds such as phenol and substituted phenols. Similarly, a 21-hydroxy pregnane can be reacted with a halide derivative of an alcohol(that is a derivative in which the hydroxyl group has been replaced byhalogen) in the presence of silver oxide.

This reaction may be effected in a solvent medium, for example in analiphatic ketone, such as acetone or methyl ethyl ketone e.g. at atemperature of to 100C.

lt will be appreciated that where it is desired to form Zl-ethers inaccordance with the invention having a water-soluble group, it may bedesirable first to form an ether having a group convertible to a groupof the lastmentioned kind; for example in the preparation of compoundshaving at position 21 a grouping carrying a primary amino substituent,for example an aminophenyl ether, it is convenient first to form thecorresponding nitro compound which can thereafter be readily reduced, inconventional manner, e.g. by hydrogenation or by chemical methods suchas reduction with a metal/acid system.

The 3a-hydroxy pregnane 2l-ethers according to the invention may also,for example, be prepared from the corresponding3Bhydrocarbon-sulphonyloxypregnane 2l-ethers by reaction with a salt ofa carboxylic acid in a manner analogous to that described by Nagata etal. (Helv. Chim. Acta., 1959, 42, 1399) followed, if desired, byhydrolysis of the 3(1-6St6l'5 so formed to liberate the 3a-hydroxygroup.

Compounds according to the invention having a 30:- hydroxy group and anSax-hydrogen atom may be prepared from the corresponding 3-oxopregnane-2lethers by stereospecific reduction using chloroiridic acid.The iridium reduction is preferably carried out by first preforminganiridium catalyst reduction system from an iridium salt or acid (e. g.chloroiridic acid), an ester of phosphorous acid (e.g. trimethylphosphite), water, and an organic reaction medium (e. g. an alcohol suchas isopropanol). This reduction system is then preferably neutralisedwith an organic base (e.g. triethylamine), and reacted with the steroid.

A still further method of preparing the 2l-ethers according to theinvention is provided by the reaction of a 203,2 l-epoxide with analcohol or phenol, preferably in the presence of an acid catalystconveniently a mineral acid such as sulphuric acid or a Lewis acid suchas boron trifluoride (as the etherate), to form a 203-01- 2 l -ether;this may then be oxidised by any reagent serving to oxidise a secondaryalcohol to a ketone, for example a chromic oxidising agent which may,for example be acidic, e.g. chromic acid in acetone, or basic, e.g.using pyridine-chromium trioxide complex in a solvent such as pyridine,benzene or methylene chloride.

During the above oxidation, the 3a-hydroxy group will normally beoxidised to a 3-oxo group but can be regenerated by stereospecificreduction; for example in the Son-series with chloroiridic acid and inthe SB-series with a borohydride. Alternatively, the 3a-hydroxy groupmay be protected, for example by conversion into a selectively cleavableester or ether group, e.g. a nitro-oxy group or an ester group of a typedesirable in the final product, e.g. an acetyl group. The nitro-oxygroup can readily be removed finally by acid hydrolysis or moreselectively, by reduction, e.g. by hydrogenation using a palladiumcatalyst or zine/acetic acid re duction. This reduction may dehalogenateany haloalkyl substituents which are present and if such substituentsare required in the final product, alternative methods will bepreferable.

The 20B,2l-epoxides may conveniently be prepared from corresponding20-ketones having at the 2 1- position a readily eliminatablesubstituent, (such as a chlorine, bromine or iodine atom or ahydrocarbonsulphonyloxy group such as a p-toluenesulphonyloxy ormethanesulphonyloxy group) by reduction of the 20- keto group (e.g.using a borohydride reducing agent, for example calcium, sodium orpotassium borohydride), the 20,8-01 so formed then being converted intothe 20B,2l-epoxide under basic conditions. Where an ll-oxo group ispresent, reduction under mild conditions will normally not attack thisgrouping but if reduction to the 1 13-01 does take place under morevigorous conditions, reoxidation can be effected simultaneously withoxidation of the ZOB-hydroxy group. The starting compound can thus carryan 1 l-hydroxy group capable of such oxidation in the final stage.

The basic conditions for epoxide formation may be achieved by adding astrong base, e.g. an alkali metal hydroxide, for example aqueous sodiumhydroxide, conveniently in an organic solvent such as tetrahydrofuran ordioxan. The reaction is often nearly quantitative. It is not necessaryto isolate the initial -01 reduction products but where it is desired toavoid reducing an 1 l-keto group, it is best to destroy any residualborohydride, e. g. by addition of an acid such as acetic acid, beforeadding the base. in some cases, the quantity of borohydride reagent usedcreates sufficiently basic conditions for epoxide formation withoutadded base.

Some ZOa-ol may be formed in the reduction and lead to a 200:,2l-epoxide, but on reaction with the alcohol or phenol it will giveproducts capable of subsequent oxidation to 20-one. Consequentlymixtures of 20aand 20B-ol do not need to be separated before basetreatment. it should be noted that the 3-position in the 20-ketostarting material may carry a protected 3a-hydroxyl group (which remainsthroughout the reaction), a or, indeed, a 3B-hydroxy group (which willbe oxidised to a 3-ketone simultaneously with the 20-ol) or a 3-oxogroup (which will be reduced to 3B- hydroxyl by the reducing agent butre-oxidised simultanteously with the 20-ol). As indicated above, 3-ketones can subsequently be stereospecifically reduced to 3ao1s.

Protection of the 3a-hydroxy group can conveniently be effected bynitration e.g. using fuming nitric acid in acetic anhydride and we havefound this reaction to proceed readily and in high yield on, forexample, 21- bromo-ZO-ketones.

it should be noted that the foregoing process in which the 20-keto groupis reduced at an early stage minimises the tendency towardsl7-isomerisation caused by enolisation at the 20-position.

The 2 l -ether substituent may, as indicated above, advantageously carrya basic substituent. This can conveniently be introduced by reacting acorresponding 21- ether carrying a readily eliminatable substituent inthe ether group (e.g. a halogen atom such as chlorine or bromine) withammonia or a suitable amine. The 21- ether starting material can be madeparticularly conveniently by reacting the 20,21-epoxides described abovewith the appropriate alcohol or phenol carrying the eliminatablesubstituent. We have found that boron trifluoride etherate is anespecially effective catalyst in this case, particularly in relation tothe reactions with ethylene chlorohydrin and 3-chloropropanol.

It is found that protection of the 3a-hydroxy group as the nitrate canreadily be adopted, as the subsequent removal by reduction with zinc andacetic acid does not attack the amino group. Alternatively, as indicatedabove, the 3a-hydroxy group can be allowed to oxidise to 3-ketone but itis then found preferable to effect stereospecific reduction to thedesired Ila-hydroxy steriod before the final reaction with ammonia or anamine.

For the introduction of a 2l-ether group carrying a carboxyl oresterified carboxyl group, a corresponding compound in which the 2l-ether group carries a cyano group may be solvolysed. The reaction ispreferably effected in the presence of an alcohol, e.g. using ethanolichydrogen chloride, to give an esterified carboyxl group which maysubsequently be converted to a carboxyl group if desired, e.g. by basichydrolysis. The cyano-ether grouping may conveniently be introduced byreacting a corresponding 20,2l-epoxide with a cyano-alcohol,advantageously in the presence of boron trifluoride etherate as acatalyst. As before, the 3a-hydroxy group may be protected or leftunprotected or a 3B-ol or 3-ketone may be used as starting msterial.

Salts of the new acidic and basic 2l-ethers may be prepared by knownmethods. Compounds of formula 1 containing a basic substituent may beconverted into acid addition salts thereof for example by reaction ofthe free base with the appropriate organic or inorganic acidconveniently in solution in an organic solvent. The preparation of saltsof 2l-ethers which contain a carboxy substituent may be effected, forexample by reaction of the free acid, conveniently in a solvent, with anappropriate base.

Substitution in the steroid molecule can be carried out in conventionalmanner, either prior to or after formation of the ether group atposition 21. Substitution at the 2-position can be effected for exampleby way of the corresponding 2a,3a-epoxy compound. The epoxy compounditself may be prepared by first dehydrating a 3a-hydroxy compound togive the corresponding A compound (e.g. by first tosylating the hydroxygroup and then detosylating the product), and then treating the Acompound with a peracid to form the 2a,3a epoxide ring. A2B-substituent, Z, may then be introduced and the Ila-hydroxy groupregenerated by reacting the 2a,3a-epoxy compound with a compound of theformula ZH or a compound furnishing an anion Z- and a cation, followed,where a metal derivative of the 3a-hydroxy group is first formed, bytreatment with a source of protons.

The 3a-acyloxy-pregnane anaesthetics may be prepared from thecorresponding 3a-hydroxy-pregnanes by acylation for example, in knownmanner. Acylation under basic conditions is generally preferred in orderto avoid undesired side reactions.

The acylating agent may for example be the anhydride or a halide(preferably the chloride) of the corresponding carboxylic acid. Ingeneral, the acylation is effected in the presence of a tertiary organicbase such as pyridine, 4-methylpyridine or N-methylrnorpholine.

The acylation is generally effected in a solvent pref erably an aproticsolvent which may, for example, be an excess of the acylating agentand/or an excess of a tertiary organic base, if desired in the presenceof a cosolvent, for example tetrahydrofuran.

Substitution at position 16 can also be carried out in conventionalmanner, various methods for this purpose being well known in the art.

Compounds in which the l6-position carries a alkyl group mayconveniently be prepared from 16,] 7-dehydro-20-oxo-steroids by reactionwith a lithium dialkyl cuprate; a 16,17-dehydro-2a,3a-epoxide reactswith this reagent to form a 2B,] a-dialkyl derivative, the two reactionsbeing effected simultaneously.

The 21-bromo steroids used as intermediates in the present processes mayconveniently be prepared by halogenation of a corresponding21-unsubstituted 20- keto pregnane, for example with molecular bromine,in an alcohol solvent advantageously in the presence of a catalyst suchas acetylchloride or hydrogen bromide. 2l-Hydroxy steroids may beobtained by lead tetraacylate oxidation of such 2l-unsubstituted 20-ket0pregnanes whereby a 2l-acyloxy group is introduced followed by basichydrolysis to yield a 21-hydroxy group. In these reactions the3a-hydroxy group is preferably protected; the nitrooxy group has provedparticularly useful and resists the basic hydrolytic conditions forremoval of the 2 l-acyloxy group. 2 l -lodo steroids can be obtainedfrom 2l-chloro steroids by halogen exchange, eg by reaction with sodiumiodide.

For the better understanding of the invention the following Preparationsand Examples are given by way of illustration only.

All temperatures are in degrees Celsius. The term petrol as used hereinrefers to petroleum ether (b.p. 60-80).

All rotations were carried out in chloroform at approximately 1% w/vconcentration unless otherwise stated:

Stock chloroiridic acid solution was prepared by refluxing a mixture ofchloroiridic acid (0.09 g.), isopropyl alcohol containing 10% water (200ml.) and trimethylphosphite (16 ml.) for 16 hours. The solution wasneutralised with triethylamine immediately prior to use.

Jones reagent refers to a solution of chromium trioxide (267 g.) in amixture of concentrated sulphuric acid (230 ml.) and water (400 ml.)made up to 1 litre with water (8N w.r.t. oxygen).

Preparative thin layer chromatography (preparative t.l.c.) was carriedout on silica gel.

PREPARATION 1 2 l Hydroxy-3a-nitro-oxy-Soz-pregnane-1 1,20-dione3a-Hydroxy-2 1 -acetoxy-5a-pregnane-l l ,ZO-dione (5 g.) in chlorofonn(25 ml.) was added to a stirred solution of fuming nitric acid (13 ml.)in acetic anhydride (50 ml.) at 5. The reaction mixture was stirred at 5for an hour, poured into stirred aqueous sodium hydroxide (l l.) andextracted with chloroform. The extract was washed with aqueous sodiumhydrogen carbonate and with water, dried (Na SO and evaporated to awhite froth. This was dissolved in methanol (500 ml. the solutionflushed with nitrogen and stirred with aqueous potassium hydrogencarbonate (17.5 ml.) for 4 hours. Glacial acetic acid (3 ml.) waasadded, the solution evaporated to small bulk, poured into water (1 l.)and extracted with chloroform, washed with water, dried (Na SO andevaporated to a white froth. Crystallisation from acetone/ether gavetitle compound (4.31 g.) as colourless irregular prisms, m.p. l74-181.

PREPARATION 2 2 1-Methoxy-3a-nitro-oxy-5a-pregnane-1 1 ,20-dionedrofuran (25 ml.) was stirred with sodium metaperiodate (1.8 g.) inwater (10 ml.) for five days. The solution was diluted with chloroform,washed with 2N- hydrochloric acid and with water, dried (Naandevaporated to a residue. Crystallisation from benzene and chloroformgave title compound (1.58 g.) as colourless rods; m.p. 2l4-2l6 (dec.);[(11 72.

PREPARATION 4 21-Diazo-3 a-nitro-oxy-S a-pregnane-l 1 ,20-dione Asolution of 3a-nitro-oxy-1 l-oxo-Sa-androstanel7B-carboxylic acid (3.5g.) in dry benzene ml.) and dry tetrahydrofuran (50 ml.) was refluxedwith oxalyl chloride (12 ml.) for 1% hours. The solution was evaporatedto give 17/3-chlorocarbonyl-3a-nitro-oxy- 5a-androstan-1 l-one as a foamwhich was dried in vacuo. A solution of this foam in benzene (100 ml.)was added to an excess of a solution of diazomethane in ether at 10. Themixture was allowed to warm to room temperature. After one hour anyexcess of diazomethane was removed by bubbling nitrogen through themixture. The solution was evaporated to a yellow foam. Purification bypreparative t.l.c. followed by crystallisation from acetone, ether andpetrol gave title compound (82 mg.) as yellow plates; m.p. l55-160 (deo)[011 PREPARATION 5 21 -Bromo-3a-hydroxy-5 a-pregnane- 1 l ,20-dione3a-l-Iydroxy-5a-pregnane-l1,20-dione (l g.) in stirred methanol (7 ml.)at 30 was treated with acetyl chloride (1 drop). After two minutesbromine (0.19 ml.) in methanol (4.5 ml.) was added dropwise. Thesolution being allowed to decolourise between the addition of each drop.The resulting clear solution was poured into chloroform (100 ml.),washed with water (3 X 50 ml.) dried (Na SO and evaporated to a whitefroth (1.40 g.). Preparative t.l.c. afforded title com pound (715 mg.)which crystallised from chloroform/ether as clusters of colourlessneedles, mp. -163; [01],, (0 0.82).

PREPARATION 6 3oz-l-lydroxy-l 6oz-methyl-5a-pregnane-l l ,20-dione To astirred slurry of cuprous iodide (950 mg.) in dry ether (75 ml.) underdry nitrogen at 0 was added a solution of methyl-lithium in ether (c1.6M; 6 ml.) until the initially formed yellow precipitate justredissolved to give a clear solution. To the stirred solution at 0 wasadded a solution of 3a-hydroxy-5apregn-l 6-ene-l l ,20- dione (600 mg.)in dry tetrahydrofuran (50 ml). During the addition a bright yellowprecipitate formed. The mixture was stirred at 0 for 30 minutes, andthen poured into cold, saturated ammonium chloride solution (200 ml.).More ether (200 ml.) was added, and the organic layer was separated,washed with saturated ammonium chloride solution (200 ml.) and withwater (200 ml.) dried over sodium sulphate and purified by preparativet.l.c. in ethyl acetate to give a product which was further purified bypreparative t.l.c. in ethyl acetate/chloroform, l/l to give a whitesolid (380 mg.) which was recrystallised from ether/petrol to give titlecompound (248 mg.) as colourless plates, m.p. 138-140, [01],, 99, (c0.95).

PREPARATION 7 203,2 1 -Epoxy3a-hydroxy-5a-pregnan-l l-one 21-Bromo-3a-hydroxy-5a-pregnane- 1 l ,20-dione (404 mg.) in methanol (25ml.) was stirred at room temperature with sodium borohydride (39 mg.) inwater ml.). After 30 minutes acetic acid (0.1 ml.) was added, thesolvents were evaporated and the residue was partitioned between waterand chloroform. The organic layer was dried (MgSO and evaporated to afroth (443 mg). This was taken up in tetrahydrofuran (25 ml.) andstirred under nitrogen with 2N aqueous sodium hydroxide (2 ml.). After 5hours the solution was partitioned between ether and water. The organicphase was washed with water, dried (Na SO and evaporated to acrystalline solid (300 mg). Recrystallisation from chloroform/ether gavetitle compound (202 mg.) as colourless rods; m.p. 235-242; (ah, 18.0, (c1.06).

PREPARATION 8 2 l -bromo-3a-nitro-oxy-SOz-pregnane-l l ,ZO-dione Asolution of 21-bromo-3a-hydroxy-Sa-pregnane- 11,20-dione (311 mg.) inchloroform (3 ml.) was added slowly with stirring to fuming nitric acid(0.8 ml.) and acetic anhydride (3 ml.), the temperature being keptbetween -5 and for 1 hour. The solution was then poured into stirredaqueous sodium hydroxide ml. 2N NaOH in 50 ml. water) to yield aresultant solution of pH 4, which was extracted with chloroform washedwith saturated sodium bicarbonate solution, water, dried (Na SO andevaporated to a white solid (324 mg.). Recrystallisation of this solidfrom acetone and petrol yielded title compound (243 mg.) as lemonirregular prisms; m.p. l2ll28; [a],,+ 108 (c 0.94).

PREPARATION 9 21-bromo-20B-hydroxy-3a-nitrooxy-5a-pregnanl l-one Asolution of 21-bromo-3a-nitrooxy-5a-pregnanel 1,20-dione (2.87 g.) inmethanol (60 ml.) and dry tetrahydrofuran ml.) was stirred with sodiumborohydride (240 mg.) in water (10 ml.). After 15 minutes, glacialacetic acid (0.3 ml.) was added and a fraction (9 ml.) of the reactionmixture was isolated. This fraction was evaporated to dryness and asolution of the residue in ether (50 ml.) was washed with water, dried(Na SO and evaporated to a white foam (261 mg.). Crystallisation of thisfoam from chloroform and ether yielded title compound (110 mg.) as whiterods; m.p. l70-174.

PREPARATION l0 203,21-epoxy-3a-nitro-oxy-Sa-pregnan-l l-one A solutionof 2l-bromo-3a-nitro-oxy-Sa-pregnanel 1,20-dione (1.01 g.) in methanol(20 ml.) and dry tetrahydrofuran (20 ml.) was stirred with sodiumborohydride (84 mg.) in water (4 ml.) at room temperature. After 1 hour,glacial acetic acid (0.1 ml.) was added and the resultant solution wasstirred, under nitrogen, with 2N sodium hydroxide (4 ml. After one-halfhour, the solvent was evaporated and the residue was stirred with water(200 ml.) for 30 minutes, filtered, washed with water and dried (756 mg.Recrystallisation of the crude product from ether yielded title compound(275 mg.) as white rods; m.p. l47l59; (ah; 23.5 (c 1.02).

PREPARATION l 1 2OB-hydroxy-21-methoxy-3anitro-oxy-Sa-pregnanl l-one Asolution of 203,2l-epoxy 3a-nitro-oxy-5apregnan-l l-one (513 mg.) in drymethanol (25 ml.) was treated with concentrated sulphuric acid (2 drops)at room temperature. After 1 hour, the solution was neutralised withsaturated sodium bicarbonate solution and the solvent evaporated. Asolution of the residue in chloroform (150 ml.) was washed with water,dried (Na SO and evaporated to a white foam (554 mg.), 209 mg. of whichwas purified by preparative t.l.c. (ethyl acetate 1:2 benzene) to yielda white foam 162 mg). crystallisation of this foam from ethyl acetateand petrol yielded title compound mg.) as white rods; m.p. 150-l55;[11],, 38 (c 1.29).

PREPARATION 1 2 21 -Methoxy-3a-nitro-oxy-5a-pregnanel 1 ,20-di0ne Asolution of 2OB-hydroxy-2l-methoxy-3a-nitrooxy- Sa-pregnan-l l-one (310mg.) in acetone (20 ml.) was stirred at 0 and treated with Jones reagentuntil oxidation was complete. The mixture was partitioned between etherand water and the ether extract was washed with water, dried (Na SO andevaporated to a white solid (222 mg.) This solid was purified bypreparative t.l.c. (ethyl acetate 1:2 benzene) and the major componentobtained was crystallised from ethyl acetate and petrol to yield titlecompound (63 mg.) as white needles; m.p. l56l62; [a] 97, (c 097).

PREPARATION l3 3a-l-lydroxy-2 l -bromo-l 6a-methyl-Sa-pregnane- 11,20-dione 3cx-Hydroxy-16a-methyl-5oz-pregnane-l 1 .20dione (5 g.) wasdissolved in dry methanol (350 ml.) and treated at 0 with a solution ofbromine (1 ml.) in dry methanol (24 ml.) at such a rate that the yellowcolour disappeared before further addition. After completion of theaddition the mixture was poured into water. The precipitated product wasdried and dissolved in chloroform 20 ml.) and put onto a column ofsilica gel MFC (700 g.). Elution with benzenezethyl acetate (2%:1) gavethe title compound (3.6 g.) as a foam, [a] 1 12.4".

EXAMPLE 1 3a-Hydroxy-2 l-methoxy-Sa-pregnane-l 1,20-dione A solution of2l-diazo-3anitro-oxy-5a-pregnane- 11,20-dione (3 g.) in dry methylenechloride (40 ml.) and dry methanol (100 ml.) was refluxed with 14% borontrifluoride methanol complex (10 ml.) for 25 minutes. The mixture wasevaporated to small volume, diluted with ether, washed with water,saturated sodium bicarbonate solution and again with water, dried (Na SOand evaporated to give 2 l -methoxy-3a-nitrooxy-Sa-pregnane-l 1,20-dioneas a solid residue.

A solution of this residue in glacial acetic acid (90 ml.) was stirredwith zinc powder (10.6 g.) for 1% hours. The mixture was filtered andthe zinc washed with chloroform. The combined filtrates were washed withwater, saturated sodium bicarbonate and again with water, dried (Na SOand evaporated to a foam. Purification by preparative t.l.c. followed bycrystallisation from ether gave title compound (530 mg.) as colourlessirregular prisms, m.p. l44-l46 [01],, 98.

EXAMPLE 2 21 -Ethoxy- 3a-hydroxy-5oz-pregnanel l ,20-dione A solution of2l-diazo-3a-nitro-oxy-5a-pregnanell,20-dione (2 g.) in dry ethanol (150ml.) was refluxed with boron trifluoride etherate (5 ml.) for 20minutes. The solution was evaporated to small volume, diluted withether, washed with water, saturated sodium bicarbonate solution andagain with water, dried (Na,SO,) and evaporated to give2l-ethoxy-3anitrooxy-Sa-pregnane-l l,20-dione as a foam. A solution ofthe foam in glacial acetic acid (50 ml.) was stirred with zinc powder(5.4 g.) for 1 /4 hours. The mixture was filtered and the zinc washedwith chloroform. The combined filtrates were washed with water, dried(Na,SO,) and evaporated to a foam. Purification by preparative t.l.c.followed by crystallisation from ethyl acetate and petrol gave titlecompound (200 mg.) as colourless plates, m.p. l29l3l [11],, 98.5.

EXAMPLE 3 3a-l-iydroxy-2 l -propoxy-5a-pregnanel l,20-dione A solutionof 21-diazo-3a-nitro-oxy-Sa-pregnanell,20-dione (900 mg.) in drypropanol (50 ml.) was treated with boron trifluoride etherate (1 ml.)and refluxed for 10 minutes. The mixture was evaporated to small volume,diluted with ether, washed with water, saturated sodium bicarbonatesolution and again with water, dried (Na SO and evaporated to a foam.Purification by preparative t.l.c. gave3a-nitro-oxy-2lpropoxy-Sa-pregnane-l l,20-dione as a foam. A solution ofthis foam in glacial acetic acid (20 ml.) was stirred with zinc powder(2.3 g.) for 1% hours. The mixture was filtered, and the zinc washedwith chloroform. The combined filtrates were washed with water, dried(Na,SO and evaporated to give title compound (480 mg.) as a white foam,[01],, 9l.5.

EXAMPLE 4 3a-Hydroxy-2 l -isopropoxy-5a-pregnane-l 1 ,ZO-dione Asolution of 21-diazo-3a-nitro-oxy-Sa-pregnanel 1,20-dione (860 mg.) indry isopropanol (60 ml.) was treated with boron trifluroide etherate (lml.) and refluxed for 20 minutes. The mixture was evaporated to smallvolume, diluted with ether, washed with water, saturated sodiumbicarbonate solution and again with water, dried (Na,S and evaporated toa residue. Crystallisation from ethyl acetate and petrol gave 30:-nitro-oxy-2 1 -isopropoxya-pregnane-l l ,20-dione (456 mg.) as off-whiterods, m.p. l35-139, [01],, 92".

A solution of the nitrate (350 mg.) in glacial acetic acid (10 ml.) wasstirred with zinc powder (12 g.) for l A hours. The mixture was filteredand the zinc washed with chloroform. The combined filtrates were washedwith water, saturated sodium bicarbonate solution and again with water,dried (Na,SO,) and evaporated to a residue. Purification by preparativet.l.c. followed by crystallisation from ethyl acetate and petrol gavetitle compound (189 mg.) as colourless rods, m.p. |2l-125, [01],, 75.4".

EXAMPLE 5 3a-l-lydroxy-2 l 2-methoxyethoxy-5a-pregnanel 1,20-dione Asolution of 2l-diazo-3a-nitro-oxy-5a-pregnanell,20-dione (500 mg.) indry 2-methoxyethanol 10 ml.) was treated with boron trifluoride etherate(l ml.) at 65'. After 10 minutes the solution was diluted with ether,washed with water, saturated sodium bicarbonate solution and again withwater, dried (Na SO and evaporated to give2|-(2'-methoxyethoxy)-3a-nitrooxy-Sa-pregnane-l l,20-dione (460 mg.) asa foam. A solution of this foam in glacial acetic acid ([0 ml.) wasstirred with zinc powder (1 g.) for 1% hours. The mixture was filteredand the zinc washed with chloroform. The combined filtrates were washedwith water, saturated sodium bicarbonate solution and again with water,dried (Na SOJ and evaporated to a residue. Purification by preparativet.l.c. followed by crystallisation from ether gave title compound (133mg.) m.p. ll5-l2l [11],, 76.7.

EXAMPLE 6 2 l -pAminophenoxy-Zia-hydroxy-Sa-pregnane-l l ,20- dione Asolution of p-nitrophenol (3.l2 g.) in ethanol (l0 ml.) and water (10ml.) was treated with 0.2N-sodium hydroxide solution ml.) and thenevaporated to a residue that was dried in vacuo. A solution of thisresidue in acetone (200 ml.) was refluxed with a solution of 2 l-bromo-3a-hydroxy-5a-pregnane-l l ,ZO-dione (1.8 g.) in acetone ml.) for30 minutes. The mixture was evaporated to small volume, diluted withchloroform, washed with water, ZN-sodium carbonate solution and againwith water, dried (Na SO and evaporated to a residue. This wastriturated with petrol and then crystallised from ethyl acetate andpetrol to give 3a-hydroxy-2 l -p-nitro-phenoxy-5a-pregnane-l l ,20-dione (1.49 g.), m.p. l86-l87, [01],, 58.5.

A solution of this l g.) in ethyl acetate 100 ml.) was shaken underhydrogen over 5% palladium-oncharcoal (100 mg.). After 4 hours themixture was filtered and evaporated to a foam. Purification bypreparative t.l.c. followed by crystallisation from ethyl acetate andpetrol gave title compound (212 mg.) as off-white plates, m.p. 1799-180,[01],, 42.5.

EXAMPLE 7 3a-Hydroxy-2 l -methoxyl Ga-methyl-Sa-pregnanel l,20-dione Thebromo-compound from Preparation 13 (3 g.) in methanol (70 ml.) and drytetrahydrofuran (15 ml.) was stirred with sodium borohydride (300 mg.)and water (10 ml.) for 30 minutes. Glacial acetic acid (0.3 ml.) wasthen added and the mixture was stirred with 2N sodium hydroxide 18 ml.),for 1 hour. The mixture was poured into water, stirred and theprecipitate was collected by filtration and dried at the pump to give20- 3,2 l -epoxy-3a-hydroxyl Ga-methyI-Sa-pregnenllone (2.7 g.), whichwas treated with dry methanol (l25 ml.) and boron trifluoride diethyletherate (2 ml. with stirring for 4 hours. The solution was neutralisedwith saturated aqueous sodium bicarbonate and evaporated. The residuewas dissolved in chloroform (250 ml. washed with water (3 X 2-00 ml.),dried (Na,. SO.) and evaporated to give 3a,20B-dihydroxy-2lmethoxyl6a-methyl-5a-pregnan-l l -one (2.4 g.

This, dissolved in acetone (175 c.c.), was treated with a slight excessof Jones reagent until the oxidation was complete. The reaction mixturewas partitioned between water and ether, the ether layer was washed withwater (3 X 300 c.c.), dried (Na S and evaporated. The total crudeproduct was refluxed for 18 hours in stock chloroiridic catalystsolution (75 c.c.). The reaction mixture was partitioned between waterand ether, the ether layer was washed with water (3 X 300 cc dried (NaSO and evaporated. The product was purified by preparative t.l.c. (ethylacetate: chloroform, 1:1) to give3a-hydroxy-2l-methoxy-l6amethyl-Sa-pregnane-l 1,20-dione (0.95 g.),[01],, 84.9".

EXAMPLE 8 3a-l-lydroxy-2l -methoxy-a-pregnan-20-one A stirred solutionof 3a-hydroxy-5a-pregnan-20-one (5 g., 15.7 mmole) in AR methanol (350cc.) was treated at 0 with a solution of bromine (1 c.c.) in methanol(23 cc.) at such a rate that the yellow colour disappeared beforefurther addition. The resultant suspension was poured into water andstirred for 30 minutes, and the precipitate was collected by filtrationand dried in vacuo. The product was purified by column chromatography onsilica gel MFC, (700 g.). Elution with benzenezethyl acetate, 1:1) gave21-bromo-3ahydroxy-Sa-pregnan-ZO-one (5.2 g.) [01],, 105.5".

The total product 5.2 g.) in methanol (200 cc) and dry tetrahydrofuran(50 c.c.) was stirred with sodium borohydride (440 mg.) and water (20c.c.). After 1 hour, glacial acetic acid (0.4 cc.) was added followed by2N sodium hydroxide (25 c.c.) and stirring was continued for a further 2hours. The solution was then poured into water (1 l.) and stirred for 30minutes, the precipitated 203,2l-epoxy-3a-hydroxy-5a-pregnane (4.9 g.)was collected by filtration and dried in vacuo (4.9 g.). [t was treatedwith A.R. methanol (225 cc) in boron trifluoride diethyl etherate (2c.c.), with stirring for hours. The solution was then neutralised withsaturated sodium bicarbonate solution and evaporated. The residue wasdissolved in chloroform (500 c.c.), washed with water (3 X 300 c.c.),dried (Na SO and evaporated to give 3a,20B-dihydroxy-2l-methoxy-5a-pregnane (3.7 g.). This was dissolved in acetone (250 cc) was treatedwith a slight excess of Jones reagent, until oxidation was complete. Thereaction mixture was partitioned between water and ether and the etherlayer was washed with water (3 X 300 cc dried (Na SO and evaporated. Theproduct was recrystallised from acetone/petroleum ether to give 21-methoxy-5a-pregnane-3,20-dione as white needles, (1.85 g.) m.p. 156,[01],, 141, (c 0.16).

The total crude product (L85 g.) dissolved in stock chloroiridicsolution (90 cc.) and the resulting solution was refluxed for 16 hours.The solution was allowed to cool and it was partitioned between waterand ether. The ether layer was washed with water (3 X 300 c.c.), dried(Na SO and evaporated. The crystalline residue was dried in vacuo andrecrystallised from acetone/petroleum ether to give3a-hydroxy-2l-methoxy-Sapregnan--one (0.84 g.), m.p. 163l 64 [a] 85.4".

EXAMPLE 9 3a-Acetoxy-2 l -methoxy-5a-pregnane-l 1,20-dione A solution of3oz-hydroxy-2l-methoxy-Sa-pregnane- 11,20-dione 0.2 g.) iii pyridine 1.0ml.) was treated with acetic anhydride (0.2 ml.) at room temperature for16 hours. The mixture was then partitioned between ether and2N-hydrochloric acid and the organic layer was washed with water, dried(Na SO and evaporated. The residue was recrystallised fromacetone/petroleum ether to give 3a-acetoxy-2l-methoxy-Sapregnane-l1,20-dione (0.17 g.) as white needles; mp. 93; [0:1 107, (c 0.7).

EXAMPLE l0 3a-Hydroxy-2B,2 1 -dimethoxy-5u-pregnane-l l ,20- dione3a-Hydroxy-2 l -methoxy-5oz-pregnane-l l ,20-dione (1.5 g.) in drypyridine (7.5 ml.) was treated with toluene p-sulphonyl chloride (1.5g.) at room temperature overnight. The reaction mixture was thenpartitioned between ZN-hydrochloric acid and chloroform, washed withwater, dried (Na SO and evaporated to give 21-methoxy-3a-(p-toluenesulphonyloxy )'5 apregnane-11,20-dione (1.55 g.) as a foam.

The total crude product in benzene was left in contact with alumina(grade H, 150 g.) for 24 hours and elution with benzene gave2l-methoxy-5a-pregn- 2-ene-1 l,20-dione (0.7 g.) as an oil.

The total product was dissolved in chloroform (25 ml.) andm-chloroperbenzoic acid (0.51 g.) was added, the solution was stirred atroom temperature overnight, diluted with chloroform, washed with dilutesodium bicarbonate, dried (Na SO and evaporated to give 211,- 3a-epoxy-2l -methoxy-5a-pregnane-l l ,20-dione (0.7 g.) as an oil.

This was stirred in dry methanol (40 ml.) and treated with concentratedsulphuric acid (0.1 ml.) for 30 minutes. The product was partitionedbetween water and chloroform.

The solvent was removed from the chloroform extract and the residue wassubjected to preparative t.l.c. in ethyl acetate-petroleum ether to givetitle compound (0.1 g.) as white needles, mp. 168-l70; [0:] 105, (c0.9).

EXAMPLE 1 l 2 l-( 2-Chloroethoxy)-3a-hydroxy-5a-pregnan-1 l ,20-dione-3-nitrate.

A solution of 208,21-epoxy-3a-hydroxy-Swpregnanll-one 3-nitrate (1.0 g.)in ethylene chlorohydrin (25 ml.) was treated with boron trifluoridediethyl etherate (3 drops) at room temperature for 1% hours. Thesolution was then partitioned between water and ether and the organiclayer was washed with water, dried (N8 S0 and evaporated.

The residue, crude 2l-(2'-chloroethoxy )-3a, 203 dihydroxy-Sa-pregnan-ll-one 3-nitrate (1.0 g.), was dissolved in acetone ml.) and treated withJones reagent 1.5 ml.) at 0 for 5 minutes. The mixture was thenpartitioned between water and ether and the organic layer was washedwith water, dried (1921 and evaporated. A portion of the residue (260mg.) was subjected to preparative t.l.c. petrol/EtOAc 2:1) to give titlecompound (0.2 g.) as a white foam, [11],, 80 (c 1.2).

EXAMPLE 12 3a-Hydroxy-2 1-(2 -morpholinoethoxy )-5a-pregnanel 1,20-dioneA solution of 21-(2'-chloroethoxy)-3a-hydroxy-5apregnane-11,20-dione3-nitrate (0.560 g.) in morpholine (8 ml.) was heated on a steam bathfor 1 hour, cooled and partitioned between water and ether. The organiclayer was washed with water, dried (Na SO and evaporated. The residuewas subjected to preparative t.l.c. (EtOAc/CHCl f(Cl-l CO, 1:1:1) togive crude 3a-hydroxy-21-(2'-morpho1ino-ethoxy)-5apregnane-l l,20-dioneB-nitrate (0.4 g.).

A stirred solution of the nitrate (0.4 g.) in acetic acid (10 ml.) wastreated with powdered zinc (1.0 g.) at room temperature for 30 minutes;poured into water, neutralised with 40% aqueous sodium hydroxide andextracted with ether. The extract was washed with water, dried (Na SOand evaporated. The residue was subjected to preparative t.l.c.EtOAc/CHC1 /(CH C0, 1:1:1, and recrystallised from acetone to give titlecompound (0.2 g.,) as slightly pink prisms, m.p. 112-1l3, [01],, 72 (c,0.9).

EXAMPLE 13 3a-Hydroxy-21-[2 N-methylpiperazino )ethoxy]-Sapregnane-l1,20-dione A solution of21-(2'-chloroethoxy)-3a-hydroxy-5apregnane-11,20-dione 3-nitrate (0.5g.) in N-methylpiperazine (10 ml.) was heated on a steam bath for 2hours, cooled and partitioned between water and ether. The organic layerwas washed with water, dried (Na:. S and evaporated.

A solution of the residue, crude 3a-hydroxy-21-[2'-(N-methylpiperazino)ethoxy1-5 a-pregnane-l 1,20- dione 3-nitrate (0.25g.), in acetic acid (10 ml.) was treated with powdered zinc (1.0 g.) atroom temperature for 45 minutes. The zinc was removed by filtration andwashed with acetic acid. The filtrate and washings were poured intowater, neutralised with 40% aqueous sodium hydroxide and extracted withether. The extract was washed with water, dried (Na SO and evaporated.The residue was subjected to preparative t.l.c. (EtOAc/CHCl;,/(CH CO,1:1:3), to give title compound (0.2 g.) as a white foam, [al 33 (c,3.0).

EXAMPLE 14 3a- Hydroxy-2 1 -methoxyfipregnane-l 1,20-dione Freshlyprepared silver oxide (690 mg.) was added to a solution of3a-acetoxy-2l-hydroxy-SB-pregnanel 1,20-dione (68.3 mg.) in methyliodide (1.5 ml.) and the resulting mixture was refluxed for 1 hour,allowed to stand overnight and then refluxed for a further 3 hours. Thereaction was partitioned between water and chloroform and the chloroformlayer was washed with water. dried (Na SO and evaporated to give 30:-acetoxy-Z l -methoxy-5B-pregnane-l 1,20-dione (69 mg.) as a foam. Thiswas dissolved in methanol (1.25 ml.) and refluxed with l0% aqueouspotassium bicarbonate solution (0.6 ml.) for 2.5 hours. The reactionmixture was allowed to cool and was partitioned between water and ether.The ether layer was washed with water, dried (Na SO and evaporated. Theproduct was purified by preparative t.l.c. (ethyl acetate:- chloroform;11] to give the title compound as a foam, [0],; 80", (c 2.36).

EXAMPLE 15 21-(2'-Cyanoethoxy)-3a-hydroxy-5a-pregnane-1 1 ,20-

dione a. A solution of 203,21-epoxy-3a-hydroxy-5apregnan-l l-one3-nitrate (1.0 g.) in ether (40 ml.) was treated with ethylenecyanohydrin 10 ml.) and boron trifluoride diethyl etherate (10 drops) atroom temperature for 2 hours. The mixture was then partitioned betweenwater and ether and the organic layer was washed with water, dried (NaSO and evaporated.

The residue, crude 21-(2'-cyanoethoxy)-3a,20B- dihydroxy-Sa-pregnan-ll-one 3-nitrate (1.3 g.) was dissolved in acetone (50 ml.), treated withJones reagent (1 ml.) at room temperature for 5 minutes and poured intowater. The precipitated solid was collected by filtration, washed withwater and dissolved in chloroform. The resulting solution was dried (NaSO and evaporated.

The less polar product, crude 21-(2'-cyanoethoxy)-3a-hydroxy-5a-pregnan-1l-one 3-nitrate (0.3 g.) was dissolved in aceticacid (8.0 ml.) and treated with powdered zinc (0.8 g.) at roomtemperature for 30 minutes. The zinc was then removed by filtration andwashed with acetic acid. The filtrate and washings were poured intowater, neutralised with 40% aqueous sodium hydroxide and extracted intoether. The extract was washed with water, dried (MgSO and evaporated togive title compound (0.2 g.) as a white foam, [01],, 87 (c 1.4).

b. A solution of 208,21-epoxy-3a-hydroxy5apregnan-l l-one (1.0 g.) inether (40 ml.) was treated with ethylene cyanohydrin (10 ml.) and borontrifluoride diethyl etherate (10 drops) at room temperature for 2 hours.The mixture was then partitioned between water and ether and the organiclayer was washed with water, dried (Na SO and evaporated. The residue,crude 2 l-( 2'-cyanoethoxy )-3a,20B-dihydroxy-5 apregnan-l l-one (0.83g.) was dissolved in acetone (60 ml.) and treated with Jones reagent(1.2 m1.) at room temperature for 5 minutes. The mixture was thenpanitioned between water and ether and the organic layer was washed withwater, dried (Na,SO.,) and evaporated.

The product, crude 21-(2'-cyanoethoxy)-5apregnane-3,1 1,20-trione (0;80g.) was treated with chloroiridic acid solution (24 ml.). The mixturewas refluxed for 24 hours cooled and partitioned between water andether. The organic layer was washed with saturated aqueous sodiumbicarbonate, water, dried (Na SO and evaporated. The residue wassubjected to preparative t.l.c. EtOAc, petrol (1:1) to give titlecompound (0.2 g.) as a white foam, [01],, (c 1.1).

EXAMPLE 1 6 2 l -[2'-(Ethoxycarbonyl)ethoxy1-3a-hydroxy-5apregnane-l 1,20-dione A solution of 21-(2'-cyanoethoxy)-3a-hydroxy-5apregnane-l1,20-dione (0.25 g.) in ethanol (10 ml.) was treated with dry hydrogenchloride at room temperature for 2 hours. The solution was thenpartitioned between water and ether and the organic layer was washedwith water, dried (Na SO and evaporated. The residue was subjected topreparative t.l.c. EtOAclpetrol 2:1, to give title compound (0.093 g.)as an oil; [01],, 57 (c 1.2).

EXAMPLE l7 21-(2'-Chloroethoxy)-3oz-hydroxy-5a-pregnane-1 1,20- dione Asolution of 208,2l-epoxy-3a-hydroxy-Sa-pregnanll-one (1.0 g.) inethylene chlorohydrin (25 ml.) was treated with boron trifluoridediethyletherate 3 drops) at room temperature for 1% hours. The solutionwas then partitioned between water and ether and the organic layer waswashed with water, dried (Na SO and evaporated. The more polar product,crude 21-(2'- chloroethoxy )-3a,20B-dihydroxy-Scx-pregnan-1 l-one (1.3g.) was dissolved in acetone (98 ml.) and treated with Jones reagent(1.8 ml) at for minutes. The resulting mixture was partitioned betweenwater and ether and the organic layer was washed with water, dried (NaSO and evaporated. The less polar product, crude 2 l-(2'-chloroethoxy)-5a-pregnane-3,l 1,20- trione (1.2 g.) was treated with stockchloroiridic acid solution (36 ml.). The resulting solution was refluxedfor 24 hours, cooled and partitioned between water and ether. Theorganic layer was washed with saturated aqueous sodium bicarbonate andwater, dried (Na S0 and evaporated. The residue was subjected topreparative t.l.c. EtOAc/petrol 1: 1, to give title compound (0.674 g.)as a white foam; [a],, 62 (c 0.9).

EXAMPLE l8 2 l 3 -Chloropropoxy)-3a-hydroxy-5 a-pregnanel 1,20-dione Asolution of 205,21-epoxy-3a-hydroxy-5a-pregnan- 1 l-one (1.0 g.) in3-chloropropanol (5 ml.) was treated with boron trifluoricle diethyletherate (6 drops) at room temperature for 5 hours. A further quantityof boron trifluoride diethyl etherate (6 drops) was added and themixture was left at room temperature for a further 1% hours. The mixturewas then poured into water and the gummy precipitate was collected byfiltration and washed with water. A solution of the precipitate inchloroform was dried (Na SO and evaporated.

The more polar product, crude 2l-(3'-chloropropoxy)-3a,20B-dihydroxy-5a-pregnan-1 l-one (1.25 g.) wasdissolved in acetone (63 ml.) and treated with Jones reagent (1.4 ml.)at room temperature for 5 minutes. The mixture was partitioned betweenwater and ether and the organic layer was washed with water, dried (NaSO and evaporated.

The less polar residue, crude 2l-( 3'-chloropropoxy)-5a-pregnane-3,l1,20-trione (1.1 g.) was treated with stock chloroiridicacid solution. The mixture was then refluxed for 24 hours, cooled andpartitioned between water and ether. The organic layer was washed withwater, dried (Na SO and evaporated. The residue was subjected topreparative t.l.c. EtOAc/petrol 1:1 to give title compound (0.54 g.) asa white foam, [01] 73 (c 1.3).

EXAMPLE 19 21-Benzyloxy-3ahydroxy-5a-pregnanel 1,20-dione A solution of20,8,21-epoxy3a-hydroxy-Sa-pregnanl l-one (0.75 g.) in benzyl alcohol(20 ml.) was treated with boron trifluoride diethyl etherate (0.3 ml.)at room temperature for 24 hours. The solution was then partitionedbetween water and ether and the organic layer was washed with water,dried Na SO and evaporated.

A solution of the residue, crude 21-benzyloxy-3a,20/3-dihydroxy-5a-pregnan-1 l-one in acetone (20 ml.) was treatedwith excess of Jones reagent (ca. 1.7 ml.). The mixture was thenpartitioned between water and ether and the organic layer was washedwith water, dried (Na SO and evaporated. The residue was purified bypreparative t.l.c. EtOAc/petrol 1:1 to give 21benzoyloxy-Sa-pregnane-3,11,20-trione as white foam which was treatedwith stock chloroiridic acid solution (30 ml. The resulting solution wasrefluxed for 16 hours, cooled and partitioned between water and ether.The organic layer was washed with water, dried (Na,, S0 and evaporated.The residue was subjected to preparative t.l.c. (CHC1 to give titlecompound (0.2 g); [11],, (0 1.4); M 230 nm. (e 900).

EXAMPLE 20 21-Cyclopentyloxy-3a-hydroxy-Sa-pregnane-1 l ,20 dione Asolution of 205', 2l-epoxy-3a-hydroxy-5apregnan-ll-one (0.75 g.) incyclopentanol (20 ml.) was treated with boron trifluoride diethyletherate (0.3 ml.) at room temperature for 24 hours. The solution wasthen partitioned between water and ether and the organic layer waswashed with water, dried (Na SO and evaporated.

A solution of the residue, crude 2l-cyclopentyloxy- 3a,ZOB-dihydroxy-Sa-pregnan-1l-one in acetone (20 ml.) was treated with aslight excess of Jones reagent (ca. 1.8 ml.). The mixture was thenpartitioned between water and ether and the organic layer was washedwith water, dried (Na SO and evaporated. The residue was purified bypreparative t.l.c. EtOAc/- petrol 1:1, to give21-cyclopentyloxy-5a-pregnane- 3,1 1,20-trione as a white foam. This wastreated with stock chloroiridic acid solution (30 ml.). The resultingsolution was refluxed for 16 hours, cooled and partitioned between waterand ether. The organic layer was washed with water, dried (Na SO andevaporated. The residue was subjected to preparative t.l.c. (CHCI togive title compound (0.3 g.); [01],, (c 1.1).

PHARMACEUTICAL EXAMPLE A 0.04 g. of 21-propoxy-3a-hydroxy-Sa-pregnane- 11,20-dione were dissolved in 2 ml. of acetone at 20C. The resultantsolution was added to 1 g. of Cremopher EL at 20C and it was stirreduntil homogeneous. The acetone was removed by a vigorous stream ofnitrogen. The solution was diluted with sterile distilled watercontaining 0.0125 g. of sodium chloride to give a final volume of 5 ml.

PHARMACEUTICAL EXAMPLE B 0.045 g. of Ba-hydroxy-Sa-pregnane-l1,20-dioneand 0.015 g. of 21-propoxy-3a-hydroxy-5apregnane- 1 1 ,20-dione weredissolved in 2 ml. of acetone at 20C. The resultant solution was addedto 1 g. of Cremopher EL at 20C and stirred until homogeneous. Thesolution was diluted with sterile distilled water containing 0.0125 g.of sodium chloride to give a final volume of 5 ml.

We claim:

1. A [3a-oxygenated pregnane-2l-ether having the general] compound ofthe formula wherein:

R is hydrogen, halogen, C -C alkanoyloxy, C -C alkoxy, C -C aklylthio, C-C alkyl or thiocyanato;"

R is hydroxy or an alkanoyloxy group of up to SC atoms or such a groupsubstituted by at least one halogen atom or carboxy or amino group;

R is hydrogen or methyl;

R is oxygen or R is a C C, alkoxy, C -C cycloalkoxy, phenyl (C -C alkoxyor phenoxy group or such a group substituted by at least one halogenatom or a carboxyl, C -C alkoxycarbonyl, C -C alkoxy or cyano group oran amino group of the formula NR"R where R and R which may be the sameor different are H or C -C alkyl or NR"R represents a piperazino ormorpholino group or such a group substituted by at least one C -C alkylgroup; and

R is hydrogen or C -C alkyl.

2. The compound of claim 1 which is 3a-hydroxy-2 l-n-propoxy-5a-pregnanel l ,ZO-dione;

3a-hydroxy-2l -methoxy-5a-pregnane-l l ,20- dione; 2 I-ethoxy-Ba-hydroxy-Sapregnane-l l ,20- dione;3a-hydroxy-2l-(2-methoxyethoxy)-5apregnanel l -dione; 2 12-chloroethoxy)-3ahydroxy-Sa-pregnane-l 1,20-dione; 21-(3-chloropropoxy)-3a-hydroxy-5a-pregnane-1 l ,20- dione;21-cyclopentyloxy-3a-hydroxy-Sapregnane-l 1 ,20-dione; or 3oz-hydroxy-2l methoxyl Ga-methyl-Sa-pregnanel l ,ZO-dione.

3. The compound of claim 2 which is 3a-hydroxy-2ln-propoxy-Sa-pregnane-1 1,20 -dione.

4. The compound of claim 2 which is 3a-hydroxy -2-l-methoxy-Sa-pregnane-l 1 ,ZO-dione.

5. The compound of claim 1 which is substituted by at least one basic oracidic group and is in the form of its salt with acid or base.

6. The compound of claim 1 wherein R is a hydroxy group.

7. The compound of claim 1 wherein R is oxygen.

8. The compound of claim 1 wherein R is a C -C alkoxy, C -C cycloalkoxy,phenyl (C -C alkoxy or phenoxy group or such a group substituted by atleast one halogen atom or a carboxyl, C -C alkoxycarbonyl, C,C.; alkoxyor cyano group.

9. A compound as claimed in claim 1 in which one of the groups R is ahydrogen atom and the other is a methyl group.

10. A process for the production of a Box-oxygenated pregnane 2l-etherpossessing a hydroxy or protected hydroxy group in the Sat-position; ahydrogen atom or methyl group at the lo-position; a hydrogen atom at thel7a-position; a keto group at the 20-position; and an etherifiedhydroxyl group at the 2l-position; which comprises the steps of:

a. reacting a corresponding pregnane having an aor B- hydroxy group,protected a-hydroxy group, or keto group at the 3-position and anepoxide group at the 20,2l-position with an alcohol or phenol to givethe corresponding pregnane-ZO-ol-Zl-ether;

b. oxidizing the pregnane-20-ol-2l-ether with a reagent serving tooxidize a secondary alcohol to a ketone to give the correspondingpregnane-ZO-keto- 2l-ether; and

c. where a 3-keto group is present in the pregnane- 20-keto-2l-etherobtained in (b), stereospecifically reducing said group to give thecorresponding 3a-hydroxy group.

11. In the processing of claim 10 the step of preparing the pregnane in(a) having an epoxide group at the 20,2l-position by reducing acorresponding ZO-keto steroid having at the 21-position a readilyeliminatable group using a borohydride reducing agent followed byepoxide formation under basic conditions.

12. The process of claim 10 wherein the alcohol or phenol used in thestep (a) carries a readily eliminatable substituent and thepregnane-ZO-ol-Zl-ether that is fonned is reacted with ammonia or anamine to give a correspondingZl-ethcr carrying a primary, secondary,tertiary or heterocyclic amino group.

13. The process of claim 10 wherein the pregnane starting material is an1 l-oxo-Sa-pregnane.

' I I I i l

1. A (3A-OXYGENATED PREGNANE-21-ETHER HAVING THE GENERAL) COMPOUND OFTHE FORMULA
 2. The compound of claim 1 which is 3 Alpha-hydroxy-21-n-propoxy-5 Alpha -pregnane-11,20-dione; 3 Alpha-hydroxy-21-methoxy-5 Alpha -pregnane-11,20-dione; 21-ethoxy-3 Alpha-hydroxy-5 Alpha pregnane-11,20-dione; 3 Alpha-hydroxy-21-(2-methoxyethoxy)-5 Alpha -pregnane-11, 20-dione;21-(2-chloroethoxy)-3 Alpha -hydroxy-5 Alpha -pregnane-11,20-dione;21-(3-chloropropoxy)-3 Alpha -hydroxy-5 Alpha -pregnane-11,20-dione;21-cyclopentyloxy-3 Alpha -hydroxy-5 Alpha -pregnane-11,20-dione; or 3Alpha -hydroxy-21-methoxy-16 Alpha -methyl-5 Alpha-pregnane-11,20-dione.
 3. The compound of claim 2 which is 3 Alpha-hydroxy-21-n-propoxy-5 Alpha -pregnane -11,20 -dione.
 4. The compoundof claim 2 which is 3 Alpha -hydroxy -21-methoxy-5 Alpha-pregnane-11,20-dione.
 5. The compound of claim 1 which is substitutedby at least one basic or acidic group and is in the form of its saltwith acid or base.
 6. The compound of claim 1 wherein R1 is a hydroxygroup.
 7. The compound of claim 1 wherein R3 is oxygen.
 8. The compoundof claim 1 wherein R4 is a C1-C6 alkoxy, C5-C6 cycloalkoxy, phenyl(C1-C6) alkoxy or phenoxy group or such a group substituted by at leastone halogen atom or a carboxyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxy orcyano group.
 9. A compound as claimed in claim 1 in which one of thegroups R5 is a hydrogen atom and the other is a methyl group.
 10. Aprocess for the production of a 3 Alpha -oxygenated pregnane 21-etherpossessing a hydroxy or protected hydroxy group in the 3 Alpha-position; a hydrogen atom or methyl group at the 10-position; ahydrogen atom at the 17 Alpha -position; a keto group at the20-position; and an etherified hydroxyl group at the 21-position; whichcomprises the steps of: a. reacting a corresponding pregnane having anAlpha - or Beta - hydroxy group, protected Alpha -hydroxy group, or ketogroup at the 3-position and an epoxide group at the 20,21-position withan alcohol or phenol to give the corresponding pregnane-20-ol-21-ether;b. oxidizing the pregnane-20-ol-21-ether with a reagent serving tooxidize a secondary alcohol to a ketone to give the correspondingpregnane-20-keto-21-ether; and c. where a 3-keto group is present in thepregnane-20-keto-21-ether obtained in (b), stereospecifically reducingsaid group to give the corresponding 3 Alpha -hydroxy group.
 11. In theprocessing of claim 10 the step of preparing the pregnane in (a) havingan epoxide group at the 20,21-position by reducing a corresponding20-keto steroid having at the 21-position a readily eliminatable groupusing a borohydride reducing agent followed by epoxide formation underbasic conditions.
 12. The process of claim 10 wherein the alcohol orphenol used in the step (a) carries a readily eliminatable substituentand the pregnane-20-ol-21-ether that is formed is reacted with ammoniaor an amine to give a corresponding 21-ether carrying a primary,secondary, tertiary or heterocyclic amino group.
 13. The process ofclaim 10 wherein the pregnane starting material is an 11-oxo-5 Alpha-pregnane.